title: Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury.
abstract: Acute lung injury secondary to sepsis is a leading cause of mortality in sepsis-related death. Present therapies are not effective in reversing endothelial cell dysfunction, which plays a key role in increased vascular permeability and compromised lung function. AMP-activated protein kinase (AMPK) is a molecular sensor important for detection and mediation of cellular adaptations to vascular disruptive stimuli. In this study, we sought to determine the role of AMPK in resolving increased endothelial permeability in the sepsis-injured lung. AMPK function was determined in vivo using a rat model of endotoxin-induced lung injury, ex vivo using the isolated lung, and in vitro using cultured rat pulmonary microvascular endothelial cells (PMVECs). AMPK stimulation using N1-(α-d-ribofuranosyl)-5-aminoimidizole-4-carboxamide or metformin decreased the LPS-induced increase in permeability, as determined by filtration coefficient (Kf) measurements, and resolved edema as indicated by decreased wet-to-dry ratios. The role of AMPK in the endothelial response to LPS was determined by shRNA designed to decrease expression of the AMPK-α1 isoform in capillary endothelial cells. Permeability, wounding, and barrier resistance assays using PMVECs identified AMPK-α1 as the molecule responsible for the beneficial effects of AMPK in the lung. Our findings provide novel evidence for AMPK-α1 as a vascular repair mechanism important in the pulmonary response to sepsis and identify a role for metformin treatment in the management of capillary injury.
authors.affiliation: Dept. of Anesthesiology, BMR II, 901 19 St., S. Birmingham, AL 35294. jcreighton@uab.edu.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Jian
authors.forename: Mikhail F
authors.initials: MF
authors.lastname: Alexeyev
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wolkowicz
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski
authors.forename: Judy R
authors.initials: JR
authors.lastname: Creighton
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D012265:Ribonucleotides / Q000494:pharmacology; D014945:Wound Healing
chemical_list: D008070:Lipopolysaccharides; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D012265:Ribonucleotides; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat; C031143:AICA ribonucleotide
keywords: acute respiratory distress syndrome; edema; endothelium; lipopolysaccharide; permeability; sepsis